Lisinopril (2) can readily be synthesized by hydrolyzing an N2- (1 (S)-alkoxycarbonyl-3-phenylpropyl)-N6; trifluoroacetyl-L-lysyl-L-proline of the general formula (1)
##STR2##
wherein R represents an alkyl group, using a base in the presence of water and then neutralizing all the basic components in the hydrolysis mixture using an acid. On that occasion, however, it is necessary, for isolating lisinopril (2), to separate lisinopril (2) from salts (salt of trifluoroacetic acid resulting from hydrolysis and salt formed from the base and acid used) which coexist in large amounts.
In that regard, the process disclosed in EP 168769 or J. Org. Chem., 53, 836 -844 (1988), for example, comprises hydrolyzing N2- (1 (S)-ethoxycarbonyl-3-phenylpropyl)-N6- trifluoroacetyl L-lysyl-L-proline with sodium hydroxide, acidifying the hydrolysis mixture with hydrochloric acid, removing all the resulting coexisting substances such as sodium chloride, trifluoroacetic acid and/or the sodium salt thereof by treatment on an ion exchange column, concentrating the organic base-containing eluate (eluent being aqueous ammonia or pyridine-water), adjusting the concentrate to the isoelectric point with hydrochloric acid and recovering lisinopril (2) by causing the same to crystallize out from the final water-ethanol mixture solution containing the amine salt formed upon the above adjustment to isoelectric point.
The above process, however, is not only complicated in operation but also poor in productivity since it is necessary to remove a large amount of salts by ion exchange treatment and the eluate is dilute, so that large-scale equipment is required and a long period and a large quantity of heat energy are wasted for the concentration of the eluate. Furthermore, the quantity of waste water to be treated, inclusive of the portion resulting from regeneration treatment of the ion exchange column, is enormous. In addition, the ion exchange column potentially poses a serious problem, namely it may readily allow various microorganisms to grow therein. In view of these and other drawbacks, the above process can hardly be said to be an advantageous one from the industrial production viewpoint.
In an another example, as disclosed in Japanese Kokai Publication Hei-08-253497, for instance, N2-(1(S)-ethoxycarbonyl 3-phenylpropyl) -N6-trifluoroacetyl-L-lysyl- L-proline is hydrolyzed with tetrabutylammonium hydroxide, which is an organic base, the hydrolysis mixture is then neutralized with trifluoroacetic acid, which is an organic acid, so that an organic salt, namely tetrabutylammonium trifluoroacetate, alone may be formed as the salt component, and lisinopril (2) is recovered by causing the same to crystallize out at the isoelectric point thereof from a mixed solvent system composed of water and ethanol in the presence of the whole amount of the organic salt.
However, the process just mentioned above, too, can hardly be said to be advantageous from the viewpoint of economy, safety and industrial practice because of the use of special reagents such as tetrabutylammonium hydroxide and trifluoroacetic acid.
Thus, in the prior art, no process is known for separating N2- (1 (S) -carboxy-3-phenylpropyl)-L-lysyl-L-proline (2) from the salt(s) mentioned above in a simple and efficient and industrially advantageous manner.
The present invention has for its object to provide a simple, efficient and industrially advantageous process for separating the salt and lisinopril (2) formed by alkali hydrolysis of N2- (1(S)-alkoxycarbonyl-3-phenylpropyl)-N6- trifluoroacetyl L-lysyl-L-proline and subsequent neutralization from the reaction mixture.